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Drugdrug Interactions Involving Transportermediated Hepatic

UPTAKE Transporter-mediated hepatic uptake can cause drug-drug interactions among drugs that are actively taken up into the liver and metabolized and or excreted in the bile. When an inhibitor of drug-metabolizing enzymes is highly concentrated in hepatocytes by active transport,

Clinical Significance of Drug Drug Interactions

Drug-drug interactions the effects of one drug on the efficacy and or toxicity of another drug have become an important issue in health care. The majority of patients are treated with more than one drug simultaneously Reasons for the treatment with multiple drugs include the treatment of multiple ailments in the same patient and the use of multiple drugs for a single ailment. With the increasing median age of the population, and the now known effectiveness of multiple-therapy regimens for viral diseases (e.g., HIV), cancer, cardiovascular diseases, and infectious diseases, exposure of a patient to multiple drugs is a common rather than rare occurrence. The need to understand the interaction potential of drugs is necessitated by events observed in the human patient population. A comprehensive review of specific cases of drug-drug interactions can be seen in Hansten and Horq (1993). Examples of drug-drug interactions with significant toxicological and pharmacological consequences are...

Minimising drug interactions

Drug selection should aim to minimise drug interactions. If it is necessary to prescribe a potentially serious combination of drugs, patients should be monitored appropriately. The mechanisms underlying drug interactions are explained in Appendix 1 (p. 800). Details of drug interactions can be found in Appendix 1 of the BNF (p. 801). Drugs and their interactions are listed in alphabetical order of the non-proprietary drug name, and cross-references to drug classes are provided where appropriate. Each drug or drug class is listed twice in the alphabetical list and also against the drug or class with which it interacts. The symbol is placed against interactions that are potentially serious and where combined administration of drugs should be avoided (or only undertaken with caution and appropriate monitoring). Interactions that have no symbol do not usually have serious consequences. If a drug or drug class has interactions, a cross reference to where these can be found in Appendix 1 is...

Drug Drug Interactions

The majority of serious cases of drug-drug interactions, as exemplified by the three specific drugs just discussed, are a result of the interference of the metabolic clearance of one drug by a coadministered drug. The interference can occur via inhibition or induction of metabolic enzymes. It is of no surprise that most known mechanisms of drug-drug interactions involve the major enzyme system for xenobiotic metabolism, the cytochrome P450 (CYP) isozymes. Although many isoforms of CYP have been discovered, most drugs are metabolized in humans by CYP isoforms belonging to the subfamilies 1A, 2A, 2C, 2D, 2E, and 3A. Of the isozymes, CYP3A, 2D6, and 2C contribute in the metabolism of the greatest number of drugs. A detailed discussion of CYP is presented in the chapter by F. P. Guengerich. A number of drug-drug interactions related to CYP involve inhibition or induction of CYP3A activity. The CYP3A subfamily is probably the most important isozyme for human drug metabolism. C YP3 A4 is...

Potential Consequences of Drug Drug Interactions

From a pharmacokinetic standpoint, the major effects of drug-drug interactions can be understood in terms of causing the disposition of a durg to be unusually slow or fast. The major consequence is a high or low plasma and tissue level of the drug. There are two other possibilities that can be considered in regard to issues of drug-drug interactions. One involves metabolism of chemical carcinogens. Most of the P450s that transform drugs can also oxidize chemical carcinogens (Guengerich and Shimada, 1991 Guengerich, 1995). The possibility exists that a P450 induced by a drug could lead to enhanced levels

Drug InteractionsP450 Metabolism

The inhibitory action of SSRIs may give rise to multiple drug-drug interactions with other medications these interactions when the drugs are coadministered may lead to no effect, intoxication, or even improving a drug's therapeutic response via a rise in its plasma concentration. Generally, SSRIs that inhibit the CYP 450 systems will impair metabolism of other medications (P450 enzyme substrates), thus prolonging their elimination half-life and increasing their blood level. For example, the SSRI inhibition of cytochrome P450 activity may lead to elevated levels of concurrently administered TCAs which are metabolized by CYP 2D6 and 3A4 isoenzymes (62). This may lead to side effects, but it may also permit clinicians to use a low-dose TCA to augment or potentiate the SSRI. Citalopram does not alter TCA levels (62). On the other hand, fluvoxamine inhibits the CYP 1A2 isoenzyme and can produce toxic levels of medications that are usually metabolized by this isoenzyme, namely tacrine,...

Highthroughput In Vitro Drugdrug Interactions 861 Inhibition

Drug-drug interactions have always been major concerns to the pharmaceutical industry. Several prominent drugs were withdrawn from the market because of serious adverse events related to drug-drug interactions. These interactions create problems for clinicians and patients and economic losses for pharmaceutical manufacturers. For this reason, pharmaceutical companies screen for enzyme inhibition and induction at the discovery stage.

Adverse Effects And Drug Interactions

Myopathy occasionally occurs in subjects taking clofibrate, gemfibrozil, or fenofibrate, and may occur in up to 5 of patients treated with a combination of gemfibrozil and higher doses of statins. Statin doses therefore should be reduced when a statin plus a fibrate are combined. Several drug interactions may contribute to this adverse response. Gemfibrozil inhibits hepatic uptake of statins by OATP2 and also competes for the same glucuronosyl transferases that metabolize most statins. Thus, levels of both drugs may increase with coadministation. Patients taking this combination should be told about potential symptoms and followed at 3-month intervals with careful history and determination of CK values until a stable pattern is established. Until there is more experience, patients taking fibrates with rosuvastatin should be followed especially closely even at low doses (5-10 mg) of rosuvastatin. Fenofibrate is glucuronidated by enzymes that are not involved in statin glucuronidation...

Transportermediated Clinical Drugdrug Interactions

Transporter-mediated clinical drug-drug interaction occur but are less frequent than metabolic drug-drug interactions. Tables 4.5 and 4.6 summarize transporter-mediated clinical drug-drug interactions. 4.6 TRANSPORTER-MEDIATED CLINICAL DRUG-DRUG INTERACTIONS 71 Table 4.5. ABC transporter mediated clinical drug-drug interactions Table 4.5. ABC transporter mediated clinical drug-drug interactions Table 4.6. SLC transporter mediated clinical drug-drug interactions Table 4.6. SLC transporter mediated clinical drug-drug interactions With the exception of OATP-mediated drug-drug interactions, transporter-mediated drug-drug interactions are of a much less severe magnitude in comparison to metabolism-based drug-drug interactions.

Predicting In Vivo Drug Interactions

In vitro data are used to predict the magnitude of in vivo metabolism-based DDIs in the clinic. No animal in vivo model is entirely suitable for assessing DDI risk in humans due to many factors, including differences in enzymes and disposition of the compound. Potential drug interactions are assessed by taking into consideration the drug as a victim or a perpetrator. There are limitations to quantitatively predict in vivo DDIs due to factors such as the involvement of transporters and uncertainty in the concentrations of the substrate and inhibitor at the active site of the enzyme. However, in addition to DDI prediction, it is possible to use in vitro data to rank order the isoforms according to inhibitory potency. This allows for clinical DDI studies to be performed first on the most potently inhibited enzyme, the outcome of which then informs further studies. This approach may prevent potentially unnecessary clinical drug interaction studies if no clinical inhibition is observed in...

Drugdrug Interactions

Sertraline has a number of drug-drug interactions of which clinicians need to be aware. Because the drug is tightly bound to plasma proteins, caution should be employed when sertraline is used in combination with pharmaceuticals possessing similar characteristics, such as warfarin, and prothrombin time should be monitored when sertraline and warfarin are used concurrently ( Zoloft 2001). The potential for serotonin syndrome may be increased when sertraline is combined with other SSRls, serotonin-norepinephrine reuptake inhibitors, or triptans used for the acute treatment of migraines. The administration of sertraline and MAOIs is contraindicated because of the significant risk of serotonin syndrome with this combination.

Physicochemical drug interactions and incompatibilities

10.2 Dilution of mixed solvent systems 401 10.8 Drug interactions with plastics 417 Chelation - in which a chelator molecule binds with a metal ion to form a complex Ion-exchange interactions - in which ionised drugs interact with opposites charged resins Adsorption to excipients and containers - causing loss of drug Interactions with plastics - another source of loss of material The chapter discusses the topic of drug interactions from a physicochemical rather than a pharmacological or pharmacodynamic viewpoint. Many drug interactions in vitro are, not surprisingly, readily explained by resorting to the physical chemistry discussed in earlier chapters of this book. There is no reason why the same forces and phenomena that operate in vitro cannot explain many of the observed interactions that occur in vivo, although of course the interplay of physicochemical forces and physiological conditions makes simple interpretations a little hazardous. Interactions such as protein binding,...

Special problems in fooddrug interaction

Hathcock, J.N. and Coon, J., Eds., Nutrition and Drug Interactions, Academic Press, New York, 1978. 11. Knapp, F.I.R., Nutrient-drug interactions, in Present Knowledge in Nutrition, 7th ed., Ziegler, E.E. and Filer, U., Jr., Eds., ILSI Press, Washington, 1996, pp. 540-546.

Drug Interactions

Other drug interactions have pharmacodynamic explanations. For example, b antagonists and Ca2+ channel blockers have additive effects on the cardiac conducting system. Additive effects on blood pressure between b blockers and other antihypertensive agents often are employed to

Organization Of The Book

These monographs are organized as follows (1) general description, (2) indications, (3) dosage form, route of administration, and dosage, (4) pharmacology and pharmaceutics (i.e., clinical pharmacology, pharmacokinetics, disposition, and drug interactions), (5) therapeutic response, (6) role in therapy, and (7) other clinical applications. Readers seeking pharmacokinetic information and additional details on molecular characteristics of biopharmaceuticals are directed to the appendices.

Abc Transporters In Drug Absorption And Elimination

Systemic exposure to orally administered digoxin is increased by coadministration of MDR1 inducers and negatively correlated with MDR1 protein expression in the intestine. MDR1 is also expressed on the brush-border membrane of renal epithelia, and its function can be monitored using digoxin ( 70 excreted in the urine). MDR1 inhibitors (e.g., quinidine, verapamil, vaspo-dar, spironolactone, clarithromycin, and ritonavir) all markedly reduce renal digoxin excretion. In view of this, drugs with narrow therapeutic windows (e.g., digoxin) should be used with great care if MDR1-based drug-drug interactions are likely.

Bloodbrain And Bloodcsf Barriers

Drugs acting in the CNS must either cross the BBB or the blood-CSF barrier, which are formed by brain capillary endothelial cells or epithelial cells of the choroid plexus, respectively. Efflux transporters play a role in these dynamic barriers. P-glycoprotein extrudes its substrate drugs on the luminal membrane of the brain capillary endothelial cells into the blood, complicating CNS therapy for some drugs (see Chapter 1). Other transporters in the BBB and the blood-CSF barrier include members of organic anion transporting polypeptide (OATP1A4 and OATP1A5) and organic anion transporter (OAT3) families, which facilitate the uptake of organic compounds such as b-lactam antibiotics, statins, PAH, H2-receptor antagonists, and bile acids on the plasma membrane facing the brain-CSF. Further understanding of influx and efflux transporters in these barriers should translate into more effective delivery of drugs to the CNS while avoiding undesirable CNS side effects and may help to define the...

Physiological Biological Principles

Metabolism at this point is called first-pass metabolism, which can limit systemic exposure for drugs despite good absorption. Oxidation, reduction, hydrolysis, and conjugation are the most common metabolic pathways, generally leading to more hydrophilic compounds that can be readily excreted renally. Cytochrome P450 (CYP) enzymes are a family of drug metabolizing enzymes that are responsible for the majority of drugs' metabolism as well as many drug-drug interactions (Shou et al., 2001 Meyer, 1996). Although the primary role of metabolism is to facilitate elimination of drugs from the body, secondary effects include transformation of drugs into other active or toxic species, which could be desirable in the case of prodrugs (Stella et al., 1985) or undesirable with respect to toxic metabolites (Kalgutkar et al., 2005). The reader is encouraged to refer to authoritative texts in this field.

Pharmacogenetic Study Design Considerations Pharmacogenetic Measures

Levels, and drug-induced gene expression patterns. Directly measuring a trait (e.g., enzyme activity) has the advantage that the net effect of the contributions of all genes that influence the trait is reflected in the phenotypic measure but the disadvantage is that it also reflects nongenetic influences (e.g., diet, drug interactions, diurnal, or hormonal fluctuation) and thus, may be unstable. For example, if a patient is given an oral dose of dextromethorphan, and the urinary ratio of parent drug to metabolite is assessed, the phenotype reflects the CYP2D6 genotype. If dextromethorphan instead is given with quinidine, a potent CYP2D6 inhibitor, the ratio may indicate a poor metabolizer genotype even though the subject carries wild-type CYP2D6 alleles. In other words, quinidine coadministration may result in a drug-induced enzymatic deficiency, and the false assignment to a CYP2D6 poor metabolizer phenotype. Lack of consistency for a given subject in a phenotypic measure, such as...

The ATP Binding Cassette Family

Penetration of several marketed drugs 4 . Interaction with P-gp can also have significant consequences in terms of drug-drug interactions 5 . Testing for P-gp inhibition in cell-based systems is now a routine in vitro screen incorporated into early phase drug discovery programmes. Following the discovery of P-gp a number of other transporters from the ABC family have also been shown to have important roles in the disposition of drugs including MRP2 (ABCC2) 6 , SPGP (BSEP, ABCB11) 7 , and BCRP (ABCG2) 8,9 . Two transporter families from the SLC group, the organic anion transporting polypeptide (OATP or SLC21, SLCO and SLC22) family 10 , and the organic cation transporter (OCT, or SLC22) family 11 , are also important in the uptake of drugs into the brain and systemic circulation.

Interactions Between Drugs

Drug interactions always should be considered when unexpected responses to drugs occur. Understanding the mechanisms of drug interaction provides a framework for preventing them. Drug interactions may be pharmacokinetic (i.e., the delivery of a drug to its site of action is altered by a second drug) or pharmacodynamic (i.e., the response of the drug target is modified by a second drug).

Bernard Testa Urs A Meyer

This book tries to give an overview on present knowledge about pharmacological and clinical aspects of antidiabetic drugs. In this connection it was found to be important to include chapters on the regulation of glucose homoeostasis and pathophysiology of Type-I and Type-II diabetes mellitus. Since diabetes mellitus is a disease of inadequate insulin secretion and inadequate action of insulin, especially in Type-II diabetes mellitus, special emphasis has been put on the molecular basis of insulin secretion and insulin actions. Several experts have contributed different topics. The clinical part was written by H. Laube, and insulin action by H. U. Haring, M. Kellerer and L. Mosthaf. The secretory machinery and mechanisms of sulphonylurea actions were contributed by H. P. T. Ammon. The author of pharmacodynamics of other antidiabetic drugs, side effects and drug interactions is E. J. Verspohl and finally M. A. Wahl added the pharmacokinetic properties of antidiabetic agents. Only...

Pharmacokinetic Interactions that Increase Drug Delivery to the Site of Action

Knowledge of the CYP isoforms that catalyze the principal pathways of drug metabolism provides a basis for understanding and even predicting drug interactions (see Chapter 3). Hepatic CYP3A isozymes catalyze the metabolism of many drugs that are subject to significant drug interactions owing to inhibition of metabolism. Drugs metabolized predominantly by CYP3A isozymes include immunosuppressants (e.g., cyclosporine and tacrolimus) HMG-CoA reductase inhibitors (e.g., lovastatin, simvastatin, and atorvastatin) HIV protease inhibitors (e.g., indinavir, nelfinavir, saquinavir, amprinavir, and ritonavir) Ca2+ channel antagonists (e.g., felodipine, nifedipine, nisoldipine, and diltiazem) glucocorticoids (e.g., dexamethasone and methylpred-nisolone) benzodiazepines (e.g., alprazolam, midazolam, and triazolam) and lidocaine. Drug interactions mediated by CYP3A inhibition can be severe (e.g., nephrotoxicity induced by cyclosporine and tacrolimus and rhabdomyolysis resulting from...

Pharmacodynamic Interactions

The oral anticoagulant warfarin has a narrow margin between therapeutic inhibition of clot formation and bleeding complications and is subject to several important drug interactions (see Chapter 54). Nonsteroidal anti-inflammatory drugs cause gastric and duodenal ulcers (see Chapter 36), and their concurrent administration with warfarin increases the risk of GI bleeding almost fourfold compared with warfarin alone. By inhibiting platelet aggregation, aspirin increases the incidence of bleeding in warfarin-treated patients. Finally, antibiotics that alter the intestinal flora reduce the bacterial synthesis of vitamin K, thereby enhancing the effect of warfarin. The number of elderly in developed nations is increasing rapidly. These individuals have more illnesses than younger people and consume a disproportionate share of prescription and over-the-counter drugs they also are a population in whom drug use is especially likely to be marred by serious adverse effects and drug...

Environmental Factors

The older anti-depressants and antipsychotics, for example, have a major metabolic clearance dependency on the polymorphic cytochrome P450 (CYP) isoenzyme CYP2D6 (Dahl et al. 2002) with other CYPs, such as CYP1A2 and CYP3A4 also contributing to this inter-variability in terms of both exposure and potential for drug interactions. All the major human drug-metabolising P450 enzymes have now been identified and cloned and the major gene variants identified. (Updated information on variant alleles in human CYPs, frequency and function can be found on the Human CYP allele Nomenclature Website, http www.imm.ki.se cypalleles). This information now provides the basis for using predictive pharmacogenetics markers to guide dose selection (Malhotra et al. 2004 Ingelman-Sundberg, 2004).

Early Clinical Development

A drug-drug interaction study is another type of clinical PK study that is typically performed on a clinical drug candidate to assess the impact of concomitant administration of other drugs on the PK behavior of the drug of interest. Interactions can arise due to metabolic factors (CYP450 interactions, enzyme induction) or competition for an active transporter. Results from in vitro screens can be used to assess the risk of drug interactions due to a CYP-related mechanism and to design meaningful clinical drug-drug interaction studies.

Adverse reactions to drugs

Established drugs and vaccines Healthcare professionals and coroners are asked to report all serious suspected reactions to established drugs (including over-the-counter, herbal, and unlicensed medicines and medicines used off-label) and vaccines. Serious reactions include those that are fatal, life-threatening, disabling, incapacitating, or which result in or prolong hospitalisation they should be reported even if the effect is well recognised. Examples include anaphylaxis, blood disorders, endocrine disturbances, effects on fertility, haemorrhage from any site, renal impairment, jaundice, ophthalmic disorders, severe CNS effects, severe skin reactions, reactions in pregnant women, and any drug interactions. Reports of serious adverse reactions are required to enable comparison with other drugs of a similar class. Reports of overdoses (deliberate or accidental) can complicate the assessment of adverse drug reactions, but provide important information on the potential toxicity of...

Definition of CYP Isozyme Specificity of Metabolism

Understanding which CYP isozyme(s) is responsible for metabolism is important in the evaluation of drug-drug interaction potential. A drug that is the substrate of a specific isozyme may compete with other drugs that are also substrates. Furthermore, drug-drug interaction is likely to occur between such a drug and known inhibitors or inducers of that specific isozyme. The definition of CYP isozyme specificity is studied using human hepatic microsomes and cDNA-expressed microsomes. With microsomes, the common approach is to evaluate whether specific inhibitors of individual isozymes would inhibit metabolism of the drug. With cDNA-expressed microsomes, microsomes containing individual isozymes are used to evaluate which isozyme would have the highest affinity and capacity for the drug (see chapters by A. D. Rodrigues and S. L. Wong and by C. L. Crespi and

Epidemiologic Overlap ofDDW Coinfection

In summary, polyparasitism may weaken the immune response, thus facilitating the establishment of a second or third infection and worsening the outcome of both diseases. Polyparasitism may introduce additional complications for the simultaneous treatment of the several coinfections, including adverse drug-drug interactions and complex administration regimens, leading to reductions in drug compliance.

Evaluation of CYP Induction Potential

A drug that induces a CYP isozyme can cause drug-drug interactions with drugs that are substrates of the same isozyme, leading to enhanced clearance. Primary human hepatocytes are the preferred experimental system for the evaluation of this aspect of drug-drug interactions. The validity of the primary human hepatocyte system as an assay for CYP induction is supported by two lines of observation (1) Known in vivo inducers of CYP, rifampin, phenobarbital, dexamethasone, phenytoin, 3-methylcholanthrene, and so on, have been found to be potent inducers of CYP in primary hepatocytes and (2) known in vivo species differences in sensitivity to inducers, e.g., differences between human and rat in response to rifampin (a potent inducer of CYP3A4 in humans but significantly less potent in rats), are observed in primary hepatocytes (see chapter by A. P. Li).

Oxidation By Cytochrome P450s

Some cytochrome P450s in the liver are induced by specific drugs, e.g. phenobarbital 2.6 while others may be inhibited by drugs, e.g. by azoles 2.7, which complex with iron. For example, the anti-ulcer drug, cimeti-dine, which contains an imidazole ring, binds to the iron of cytochrome P450s. This alters the metabolism and hence biological activity of other drugs. Ethanol and a constituent of grapefruit juice, nootkatone, also have an effect on cytochrome P450s. This can lead to an altered pattern of drug metabolism and to drug drug interactions.

Conclusions and Future Directions

The clinical importance of drug-drug interaction is well recognized. Recent major advances in this field have been (1) a better understanding of the mechanism of interactions and (2) the application of the mechanistic knowledge toward developing logical and scientifically acceptable approaches for evaluating new and existing drugs for their potential to interact with other drugs. This mechanistic approach is an important scientific advancement. It would be impossible to evaluate experimentally the interaction of a new drug with all existing drugs, and it would not be prudent to wait until significant drug interactions are observed in the clinic. The logical prediction of drug-drug interactions based on knowledge of the metabolic pathway and the ability of the drugs in question to inhibit or induce key metabolic enzymes remains the most promising approach (see chapters by T. N. Thompson J. D. Balian and A. Rahman and M. Jurima-Romet). under what circumstances, and via which mechanism,...

Important definitions and terms

Experimental methods applied within molecular biopharmaceutics were initially taken primarily from physical chemistry and physiology but related to aspects of interest for studying steps of importance for bioavailability, namely drug absorption, distribution, metabolism and elimination (ADME). Thus, physicochemical and physiological phenomena, for example acid base properties, solubility, partition, stability and permeability within physiologically relevant environments, and of relevance for ADME, are studied. Biochemical and molecular biology methods have also been employed over recent years to study ADME phenomena such as absorptive, metabolic, distributive and eliminative pathways as well as expression of endogenous enzymes and transporters of relevance to ADME. Thus, modern molecular biopharmaceutical science is interdisciplinary and methods applied in the field are also applied and relevant to industrial preclinical and (pre)formulation drug development. Regulatory authorities...

Preformulation Testing Criteria

The classical preformulation studies include the physicochemical characterization of the solid and solution properties of compounds that would be useful in formulating the drug into a suitable delivery system. It is in this critical decision-making about what constitutes the suitable that many a lead compound falls through. A good pharmacological and toxicological profile alone does not suffice. The drug delivery system must be able to take the molecules to the site of action, at a cost and convenience commensurate with the treatment trends. An excellent remedy for headache that requires intravenous injection would not go past this stage on the other hand, for those drugs where there are no alternatives, such as in cancer treatment or other diseases where the patient is hospitalized and critically ill, any dosage form would be acceptable if cost and reimbursement issues do not impair the commercial projections of sales. Besides delivering the drug, the dosage form must provide a...

Use of Information about Human P450s

The acquisition of the in vitro information about a new drug can be extremely useful. In many cases, the FDA now expects in vitro information on the P450s involved in the oxidation of a drug early in the registration process. The in vitro information can be used to guide the more expensive and time-consuming in vivo studies. In particular, potential adverse drug interactions due to pharmacokinetics can be predicted and the number of in vivo interaction studies can be restricted, as some of those historically done with all new drugs may be found irrelevant. The in vitro procedures, if used early in the drug development process, may be used to select from a series of potential candidates, in terms of which will be least likely to cause problems with drug-drug interactions. Another point is that the in vitro studies can be used as a guide in predicting bioavailability, simply by screening candidate drugs for resistance to oxidation by the major known human P450s.

Signaling Responses Based on Activation of Phospholipase Cb

A broad range of hormones, neurotransmitters, growth factors, chemoattractants, and other extracellular stimuli produce their physiological responses, at least in part, through activation of phospholipase C. This activation produces Ins(1,4,5)P3 and diacylglycerol as the immediate dual second messengers and mobilized intracellular Ca2+ and activated protein kinase C as the second pair of messengers (39,40). These two secondary signaling species then promote a remarkably broad set of biochemical responses that include activation of other second messenger pathways including, for example, those concerned with activation of phospholipase A2 or phospholipase D. As a consequence, interaction of molecules with receptors that couple to phospholipase C theoretically can be assessed by quantitation of many different biochemical responses. There are strong arguments that biochemical assessment of drug interaction of Gq-coupled receptors should be restricted to quantitation of the biochemical...

Class ADisease Specific

A disease specific molecular target should be a molecule that operates only in the disease state and is not participating in physiological (normal) functions. Drug interaction with such targets should provide efficacy with the lowest chance for mechanism-based adverse effects when manipulated by drugs. Examples of such targets are genetic disorders, which result in either over-activity or loss of activity of the target. Such is the case in Chronic Myelogenous Leukemia (CML) that results from aberrant recombination of DNA from chromosome 22 into chromosome 9 (Philadelphia Chromosome), fusing the Bcr and Abl genes into an overacting tyrosine kinase, which drives oncogenic transformation. To cure the disease, potent and selective inhibitors of this aberrant kinase had to be discovered, a task that took over a decade to accomplished.13 Such targets have the potential for a high safety profile. It is however, important to note that this example may does not necessarily represent the...

Combination Treatment of Cholinesterase Inhibitors with Memantine

Memantine has a distinct mechanism of action. It is a noncompetitive N-methyl-D-aspartate receptor antagonist. As more data become available from recent research, it is now known that other neurotransmitters, besides acetylcholine, are involved in Alzheimer's disease. In the glutamate hypothesis, excessive activation of NMDA by glutamate is implicated in neurotoxicity and neuronal ischemia. Normally, NMDA receptors are activated by glutamate, which is an excitatory neurotransmitter in the brain. Thus, by blocking this excessive activation, memantine may have a neuroprotective effect 67 . Currently in the United States, memantine is approved for treatment in moderate to severe Alzheimer's disease. Since memantine works via a different mechanism than cholinesterase inhibitors, combining the two medications may enhance efficacy of treatment in Alzheimer's disease 68 . In a drug interaction study, adding memantine to galantamine appears to be safe. There was no significant change in the...

Analysis of Ligand Receptor Interaction Utilizing Cell Signaling Responses

Of studies directed at the signaling specificity or biological regulation of heterologously overexpressed receptors is a concern, the value of such cell lines as sensitive indicators of drug interaction at GPCR is considerable. This enhanced sensitivity is most applicable for receptor agonists and follows from the high level of overexpression of receptors that can be attained with mammalian cell expression vectors.

Agagatgtaattaaatgtatac3

Genetic sequence variation may provide useful information to assist in making clinical decisions about drug treatment. Like all possible prognostic markers, the effect of polymorphisms on clinical endpoints must be validated through several preclinical and clinical processes mentioned in the following subheadings. Studies of the pharmacogenetics of transporters should (1) establish theoretical and experimental evidence that a transporter polymorphism is associated with interindividual variability in drug treatment (2) establish drug interaction with a transporter Polymorphic efflux of ABCB1 substrates was initially evaluated using flow cytom-etry, although such assays are limited in that only fluorescent compounds can be assayed, and differences in polymorphic transporter expression and function are not made clear. To date, the influx of rhodamine 123, calceine, doxorubicin, and daunorubicin has been evaluated using such methods and are still used in drug-drug interaction studies. The...

Clinical Assessment

If the study drug is an inhibitor or substrate of a cytochrome P450 isoenzyme at clinically relevant drug concentrations and pharmacokinetic phar-macodynamic drug interaction studies are planned, consideration should be given for collection of ECGs in these studies as well. ECGs should be obtained concurrently with plasma drug concentrations of the study drug and the other drug.

General comments on pregabalin and gabapentin

Systematic reviews and meta-analysis have confirmed the efficacy of both drugs in neuropathic pain, including central pain. 9 I , 15 I , 16 I , 30 I Emerging evidence suggests an effect superior to placebo in some non-neuropathic pain conditions.48,4950 There is little difference to be found between the two drugs, either in indications, contraindications, efficacy, tolerability, or drug interactions (Tables 19.2 and 19.3). The arguably more straightforward pharmacokinetics of pregabalin offers some benefits but with a patient who will need individual titration anyway, this may not be decisive. The relative safety and lack of interactions are properties that justify choosing either pregabalin or gabapentin as a firstline treatment in neuropathic pain, with good potential to be used in combination therapy if needed (Table 19.1).

C 17aEthynylestradiol

This is a classic example of a drug-drug interaction and one of the few attributed to induction, instead of inhibition. In the early 1970s several German reports indicated that women who were using oral contraceptives began spotting or became pregnant after using rifampicin or barbiturates (Reimers and Jezek, 1971 Nocke-Finck et al, 1973 Janz and Schmidt, 1974). The major estrogen in oral contraceptives is 17a-ethynylestradiol (Fig. 4), which is metabolized via 2-hydroxylation, plus other pathways (Bolt et al., 1973 Guengerich, 1990b). Administration of rifampicin resulted in the faster elimination of 17a-ethynylestradiol in volunteers (Bolt et al., 1977).

Milnacipran Analogues

Milnacipran 12, a dual SNRI, is approved for the treatment of depression 42 and is currently in phase 3 trials for the treatment of fibromyalgia 43 (Fig. 15). Interestingly, milnacipran is a polar compound with a log D of 0, and as such is different from many other centrally acting monoamine reuptake inhibitors which are far more lipophilic. The polar nature of mil-nacipran delivers an attractive PK profile in humans, with high bioavail-ability, long half-life and renal elimination of unchanged drug as the primary route of clearance 44 . Despite its polar nature, milnacipran is still believed to exert its pharmacology via central inhibition of serotonin and noradrenaline reuptake. The lack of interaction of milnacipran with P450 enzymes as either substrate or inhibitor reduces the potential for drug-drug interactions, which are highly prevalent for many other marketed monoamine reuptake inhibitors. This attractive physicochemical and PK profile, coupled with clinical efficacy, has...

Membrane Based Systems

Immobilised artificial membrane (IAM) surfaces are constructed of phospholipid analogs which are covalently bound by an alkyl chain to silica particles at high molecular surface densities, mimicking fluid phase phospholipid bilay-ers (Pidgeon and Venkataram, 1989 Taillardat-Bertschinger et al., 2003). Even given the advantages of IAM, including the ease of automation, the speed of screening, and the possibility to study pH-dependent partitioning, the data obtained with IAM chromatography may not always reflect biological permeation but only drug interactions with the membrane surface. Other shortcomings associated with the method include column variability and instability.

Enzymes Performing Amino Acid Conjugates

Williams JA, Hyland R, Jones BC et al (2004) Drug-drug interactions for UDP-glucuronosyltransferase substrates a pharmacokinetic explanation for typically observed low exposure (AUCi AUC) ratios. Drug Metab Dispos 32 1201-1208 Zhang J, Cashman JR (2006) Quantitiative analysis of FMO gene mRNA

Other Antidepressants

Ise with respect to efficacy in neuropathic pain (Semenchuk et al. 2001) (see Table 5-6). Bupropion lacks significant cardiac or anticholinergic side effects and has fewer risks of drug interactions however, there is a risk of seizure associated with higher doses. The MAOI phenelzine has been found to be effective in the treatment of selected pain disorders. However, MAOI use has been limited by medication side effects, the need for a tyramine-free diet, and the potential risk of drug interactions (e.g., serotonin syndrome arising from coadministration with me-peridine).

Conclusions and Perspectives

Dollars are spent before a new biopharmaceutical is approved for human use elaborate studies are performed to examine the biology, toxicology, potential drug-drug interactions, and patient populations. It is therefore somewhat surprising that so little is actually understood about the fate of a protein or peptide therapeutic after injection into the SC space. Efforts to formulate these materials are primarily focused on shelf-life stability and lack of pain upon injection. As these injected materials are endogenous (or at least composed mostly of endogenous elements), there is the perception that they will readily find their way to their intended pharmacological target once they are placed in the body. Concerns over events that might occur at an SC injection site are only of issue when the protein or peptide being administered fails to be efficacious or incites an immune response.

Caco2 Drug Transport Assays

The Caco-2 cell line is heterogeneous and was derived from a human colorectal adenocarcinoma. Caco-2 cells are used as in vitro permeability models to predict human intestinal absorption because they exhibit many features of absorptive intestinal cells. This includes their ability to spontaneously differentiate into polarized enterocytes that express high levels of brush border hydrolases and form well-developed junctional complexes. Consequently, it becomes possible to determine whether passage is transcellular or paracellular based on a compound's transport rate. Caco-2 cells also express a variety of transport systems including di-peptide transporters and P-glycoproteins (Pgp). Due to these features, drug permeability in Caco-2 cells correlates well with human oral absorption, making Caco-2 an ideal in vitro permeability model. Additional information can be gained on metabolism and potential drug-drug interactions as the drug undergoes transcellular diffusion through the Caco-2...

The Biopharmaceutics Drug Classification Systems

The BDCS should serve the needs of the earliest stages of discovery research where it can be useful in predicting routes of elimination, effects of efflux, and absorptive transporters on oral absorption, when transporter-enzyme interplay will yield clinically significant effects, such as low bioavailability and drug-drug interactions, the direction and importance of food effects, and transportor effects on postabsorption systemic levels following oral and intravenous doses.

Special Challenges in TB Drug Development

One of the most pressing issues in improving TB chemotherapy involves the use of RIF (see Sect. 2.1 for further discussion of development of RIF as a chemother-apeutic agent), the most effective drug in reducing patient bacillary burdens in the first-line regimen for drug-susceptible TB. Recent studies indicate that treatment outcomes worsen with reduced durations and intermittent use of RIF 65 . Reducing RIF treatment to 1-2 months results in increased rates of relapse and acquired resistance compared to established regimens using RIF for a 6-month period. Additionally, intermittent weekly or twice weekly administrations may promote relapse and acquired resistance. Although RIF is an essential drug in first-line therapy for establishing a positive treatment outcome, use of RIF in combination with various drugs is problematic because of drug-drug interactions as a consequence of RIF's powerful induction of many cytochrome P450 (Cyp) enzymes. These enzymes metabolically inactivate...

Variability In The Doseeffect Relationship

The development of single-isomer drugs may offer advantages over use of the racemic mixture. Potential advantages include a less complex and more selective pharmacological profile, a potential for an improved therapeutic index, a more simplified pharmacokinetic profile, a reduced potential for complex drug interactions, and a more definable relationship between plasma drug concentration and effect. Examples of racemic mixtures in current use include methadone, methylphenidate, bupropion, venlafaxine, fluoxetine, and citalopram. Clearly, each drug needs to be considered individually with regard to its development as a single stereoisomer formulation. Recent examples of successful switches to single isomers are escitalopram and dexmethylphenidate.

Atomoxetine Analogues

Assessment of compound 107 for selectivity against a panel of amine neurotransmitters revealed activity for the 5-HT2B receptor (IC50 250 nM). It is important to note that no functional 5-HT2B was reported, but should 107 prove to be a potent agonist at the 5-HT2B receptor then it is likely to possess an unacceptable safety risk for cardiac toxicity 93 . Additional screening of 107 in in vitro ADME assays showed 107 to be a CYP2D6 inhibitor (IC50 250 nM) and it was concluded that this level of inhibition could lead to potential drug-drug interactions.

In Vitroin Vivo Comparisons

One general problem involves approaches to searching for possible drug-drug interactions. Ideally this should be done first in in vitro settings to expedite the process, and some approaches looking for enzyme inhibition and induction have been mentioned (vide supra). However, there is the matter of validation of in vivo results in in vivo settings.

Summary and Conclusions

Many adverse drug-drug interactions are attributable to pharmacokinetic problems and can be understood in terms of alterations of P450-catalyzed reactions. Much is now known about the human P450 enzymes and what they do, and it has been possible to apply this information to issues related to practical problems. A relatively small subset of the total number of human P450s appears to be responsible for a large fraction of the oxidation of drugs. The three major reasons for drug-drug interactions involving the P450s are induction, inhibition, and possibly stimulation, with inhibition appearing to be the most important in terms of known clinical problems.

High Throughput Assays

Due to the escalating cost of bringing new drugs to the marketplace, the pharmaceutical industry has sought mechanisms to identify, early in the drug discovery process, compounds that are likely to fail in the clinic. Thus, in vitro metabolic clearance and P450 inhibition assessment have been implemented to identify those compounds that are likely to demonstrate the desired human exposure profile and a low likelihood of involvement in drug-drug interactions 29 . Implementation of the in vitro clearance assay has been fueled by its simplistic experimental design, compatibility with automated high-throughput screening formats, and concomitant advances in analytical and data-processing capabilities 30-34 . These assays tend to be performed in the presence of commercially available hepatic microsomal or S9 fraction, or hepatocytes 35-37 obtained from preclinical animal species and human. Microsomal or S9 fraction incubations tend to be the most commonly used early in the drug discovery...

Pharmacology and pharmaceutics

Drug interactions Because of its ability to potentiate myeloproliferative effects, lithium should be used cautiously in patients also receiving sargramostim. Severe atypical peripheral neuropathy was reported to occur significantly more commonly in patients with lymphomas receiving a colony-stimulating factor (sar-gramostim or filgrastim) with vincristine than vincristine alone.

Box 261 Communicable Disease Council AIDS indicator conditions for adolescents and adults2

Although there is no cure for HIV, effective suppressive antiretroviral treatment has been available since the mid-1990s. Antiretroviral treatment is associated with considerable adverse effects and a propensity for drug interactions. HIV is a rapidly evolving virus with a tendency to mutate hence combinations of at least three Despite the availability of antiretroviral therapy, illness and pain occur as a direct consequence of the viral toxi-city, concurrent illness, drug adverse effects, and immune recovery. Pain is frequently reported in HIV disease and the experience of pain increases with advancing disease.4 Principles of pain management in the context of HIV are similar in many ways to those of pain management in other scenarios. However, painful peripheral neuropathy is common in HIV and requires particular attention, as does the potential for serious drug interactions with HIV therapy.

Class A Disease Specific Target

A disease-specific molecular target should be a molecule that operates only in the disease state and does not participate in physiological (normal) functions. Drug interaction with such targets should provide efficacy with the lowest chance for mechanism-based adverse effects when manipulated by drugs. Examples of such targets are genetic disorders, which result in either overactivity or loss of activity of the target. Such is the case in chronic myelog-enous leukemia (CML), which results from aberrant recombination of DNA from chromosome 22 into chromosome 9 (Philadelphia chromosome), fusing the Bcr and Abl genes into an overacting tyrosine kinase, which drives onco-genic transformation. To cure the disease, potent and selective inhibitors of

Aldosterone Antagonists

A principal feature of CHF is marked activation of the renin-angiotensin-aldosterone system. In heart failure patients, plasma aldosterone concentrations may increase to as high as 20 times the normal level. Aldosterone has a range of biological effects beyond salt retention (Table 33-2), and antagonism of aldosterone's actions may be beneficial in patients with heart failure. The beneficial effects of spironolactone on mortality appear to be additive to those of ACE inhibitors and b receptor antagonists in patients with symptomatic heart failure the use of spironolactone should be considered in patients with NYHA Class III and IV heart failure. Caution should be exercised when significant renal impairment is present. Treatment is initiated at a dose of 12.5 or 25 mg daily, as higher doses may lead to hyperkalemia, particularly in patients receiving an ACE inhibitor. Serum K+ levels and electrolytes should be checked after initiation of treatment, and vigilance is warranted for...

Management of the Psychotic Patient

Summary This article reviews the pharmacologic management of the psychotic patient, to familiarize oral and maxillofacial surgeons with the care of these patients. The author notes that the trend to outpatient care extends to the psychiatric patient and more health care providers will be faced with the care of this patient population. The author reviews potential drug interactions and clinical considerations for patients already under maintenance therapy. The article covers antipsychotic agents, mood disorders, HCAs (including tricyclic drugs), MAOIs (derivatives of hydrazine or amphetamine), SSRIs (antidepressants), bipolar disorder, and antianxiety agents, specifically benzodiazepines, barbiturates, and buspirone. The emphasis in each section is on pharmacodynamics, drug interactions, and anesthetic concerns. 3 tables. 25 references.

Intervention supported by evidence

Oxcarbazepine, which is a daughter drug of carbamazepine, has been evaluated in RCT and a small systematic review (all abstracts) comparing it to carbamazepine. It has some improved efficacy over carbamazepine and much better tolerability. Oxcarbazepine has a much lower potential for drug interactions as it does not rely on the liver cytochrome system. A small RCT using gabapentin in combination

Clinically important interactions involving new antiepileptic drugs

During the last decade, about 10 new antiepileptic drugs have been developed and introduced for clinical use. The new antiepileptic drugs have improved the treatment of epilepsy in several respects. First, they improve seizure control in patients, who continue to experience seizures despite treatment with old antiepileptic drugs.6,8 Second, new antiepileptic drugs have an improved side-effect profile. Several double-blind controlled studies have shown that patients receiving new antiepileptic drugs experience fewer side-effects than patients treated with old antiepileptic drugs.9-10 Third, new antiepileptic drugs have significantly less interactions with other drugs. In contrast, old antiepileptic drugs are notorious for their drug interactions, including significant interactions with other antiepileptic drugs. For example, phenytoin decreases the levels of carbamazepine, oral contraceptives, valproate, warfarin and many other medications that are metabolized in the liver.11

Clinical pharmacology According to

Drug interactions Concomitant treatment with thrombolytic agents may increase the risk of bleeding complications and considerably enhance the effect of Refludan on aPTT prolongation. Concomitant treatment with coumarin derivatives (vitamin K antagonists) and drugs that affect platelet function may also increase the risk of bleeding.

Metabolism Based Drus Interactions

One of the main types of drug-drug interaction (DDI) is pharmacokinetic DDI, in which one drug alters the pharmacokinetics of another drug. Here, we discuss about the two main modes of pharmacokinetic DDIs The most understood and studied DDI is the metabolism-based type. Here, we discuss inhibition, induction, and reaction pheno-typing in an in vitro setting. We also discuss in vivo drug-drug interaction predictions based on in vitro data. Useful tables of probe substrates, selective inhibitors, and inducers are included. 5.7 Predicting In Vivo Drug Interactions 88

Basic Concepts And Definitions

Metabolism is one of the major routes of eliminating a drug from the body. For most drugs, only a few enzymes mediate the metabolic pathways therefore, coadministration of drugs can potentially lead to metabolism-based DDIs. Thus, the assessment of drug interactions in the drug discovery phase, as well as in the clinic, is a necessary part of providing safe and effective drugs to the market. Many parameters are involved in this assessment, taking into consideration the role of each drug as either a victim (i.e., substrate or

Membrane transport of drug candidates

Membrane transporters are important for bioavailability of drug substances, classifications of transporters via classical functional concepts as well as genetic concepts are provided. The last chapter of this section is about the preclinical evaluation of drug transport. This chapter gives an industrial perspective on how drug candidates are evaluated in terms of transport properties as well as metabolism. The impact of transporters on bioavailability and potential risk of transporters as mediators of drug-drug interactions have also gained the attention of the regulatory authorities. A draft Guidance for Industry from the US Department of Health and Human Services, Food and Drug Administration (FDA), Center for Drug Evaluation and Research (CDER) and Center for Biologics Evaluation and Research (CBER) states . . . not every drug-drug interaction is metabolism-based, but may arise from changes in pharmacokinetics caused by absorption, distribution and excretion interactions. Drug-drug...

Nonopioid Analgesic Agents

Systemic side effects or drug-drug interactions. In double-blind randomized controlled studies the lidoderm patch was evaluated as an adjunctive add-on medication for the treatment of chronic peripheral neuropathic pain syndromes from various causes and found to be effective in reducing both ongoing pain and allodynia (Meier et al. 2003).

Phenotyping of Cytochrome P450 Isoforms

Despite the fact that many of P450 isoforms exhibit partially overlapping substrate specificity, it has become apparent that in most cases a single P450 isoform may be exclusively or primarily responsible for metabolism of a particular drug at therapeutic concentrations in vivo (Parkinson, 1996b Guengerich, 1996). Information on P450 isoform(s) responsible for the metabolism of the drug of interest is important for an understanding of two critical aspects of drug metabolism in humans. (a) drug-drug interaction in metabolism between coadministered drugs, and (b) metabolic polymorphism of a drug. Four in vitro methods have been used for phenotyping P450 isoforms, and a combination of at least two different approaches is generally necessary to identify the P450 isoform(s) responsible for the metabolism of the substrate of interest.

Tricyclic And Tetracyclic Drugs Introduction

The tricyclic antidepressant agents hold an important place in the history of treatments for depression. They were the first class of antidepressant compounds to be widely used in depression and remained the first-line treatment for more than 30 years. The observation of their activity led to theories of drug action involving norepinephrine and serotonin. Indeed, this psychopharmacological bridge suggested that alterations of these neurotransmitters might cause depression (Bunney and Davis 1965 Prange 1965 Schildkraut 1965). The tricyclics were extensively studied, and through this study the field developed several principles for the management of depressive illness. For example, in addition to understanding the need for adequate dose and duration during acute treatment, the importance of continuation treatment was described. The adverse events associated with these agents required that psychiatrists become familiar with a variety of syndromes, such as anticholinergic delirium,...

Management and prognosis

Carbamazepine has been used extensively in the management of TN and with good success. Several meta-analyses are available and generally agree that about 70 percent of patients will benefit from therapeutic doses (100-2400 mg).100 I The NNT value is accordingly good in the range of 1.8 (1.3-2.2 95 percent confidence interval). However, side effects are frequently observed such as allergic rash, hyponatremia, and numerous drug interactions, so elderly patients in particular must be monitored carefully. A second choice may be oxcarbazepine which also has been documented to be effective in a number of RCT studies.100 I Other options are lamotrigene, baclofen, and topiramate.103

Interactions Between Opioid And aOpioid Agonists

Demonstrated an enhanced antinociceptive effect of ICV morphine or DAMGO by ICV DPDPE, which was blocked by ICI 174,864 87,100,140, 141 . As would be expected in drug interaction studies, the level of synergy or additivity was found to be sensitive to the drug ratio employed and to the test used 106 . For example, although a 1 5 ICV ratio of DPDPE to morphine was synergistic in a cold-water tail flick test, a 2 5 ratio was not 106 . The ICV administration of fixed ratios of morphine with either DPDPE or D-Ala2, Glu4 deltorphin produced a synergistic antinociceptive effect in the mouse 142 . In contrast, the combination of Met5 enkephalin with morphine was found to be subadditive in the same study 142 . A particularly impressive demonstration of such synergy was shown when systemic Leu5 enkephalin, inactive alone, produced synergy with systemic morphine, as quantified by isobolographic analyses 143 . The synergy, but not the effect of morphine, was blocked by ICV ICI 174,864 143 .

Evaluation of Drug Combinations

Compounds involved.37 Thus, during preclinical evaluation, a novel antiepileptic drug should not only be tested alone but also in combination with standard antiepileptic drugs in order to study drug interactions in terms of anticonvulsant activity and adverse effects.37 For this purpose, the same test procedures described above for single drug experiments can be used.37 However, in view of the fact that for preclin-ical evaluation of drug combinations each drug of a two-drug combination has to be tested at different dose levels, the necessary number of animal experiments is so high that polypharmacy testing should start with simple models for neurotoxicity testing, such as the rotarod test.37 We have recently described a suitable test strategy for evaluation of antiepileptic drug combinations.37

Chemotherapy Of Tuberculosis

Drug interactions are a special concern in patients receiving highly active antiretroviral therapy (HAART). The rifamycins accelerate the metabolism of protease inhibitors and nonnucleoside reverse transcriptase inhibitors. Rifabutin has the least effect on serum levels and is indicated in this setting.

Antibacterialactivity And Bacterial Resistance

Therapeutic uses Rifabutin is effective for the prevention of MAC infection in HIV-infected individuals and can decrease the frequency of MAC bacteremia. Azithromycin or clarithromycin is more effective and less likely to interact with HAART drugs. Rifabutin also is commonly substituted for rifampin in the treatment of tuberculosis in HIV-infected patients, as it has a less profound CYP-dependent drug interaction. Rifabutin also is used in combination with clarithromycin and ethambutol for the therapy of MAC disease.

Chemotherapy Of Mycobacterium Avium Complex

Clarithromycin and azithromycin both have excellent activity against many strains of MAC, with clinical responses (decrease or elimination of bacteremia, resolution of fever and night sweats) demonstrated even with single-drug therapy. To avoid resistance, most clinicians treat disseminated MAC infections with clarithromycin or azithromycin plus ethambutol. In some situations, rifabutin, clofazimine, and or a quinolone are added. Drug interactions and adverse drug reactions are common with multiple-drug regimens, necessitating drug discontinuation in 50 of patients. Clinical improvement is expected in the first 1-2 months of treatment, with sterilization of blood cultures within 3 months of starting therapy. Treatment of MAC infection in HIV-infected individuals typically is lifelong. Isoniazid and pyrazinamide have no role in the treatment of MAC infection.

Dopamine Transporters DATs

High binding of DAT radiotracers has been found in the caudate and putamen, regions known to have a high density of the DAT 48 . The striatum is thus a suitable region for determination of changes of DAT binding as a result of drug interactions. Phenyltropane is one of the chemical scaffolds that has been applied for the development of selective tracers for DAT. The cocaine analogues, such as P-CFT P-CIT and RTI-121 (3P-(4-iodophenyl)tropane-2P-carboxylic acid isopropyl ester) have been extensively used as markers of DAT in animals or in the human brain (Fig. 6). In vivo studies with both SPECT and PET have been performed in monkeys and humans, particularly using P-

Effect Of Type I Interferons On The Cyp450 System

IFN-a and IFN-b are considered type I IFNs and belong to the larger helical cytokine superfamily that includes GHs, ILs, several colony-stimulating factors, and several other regulatory molecules. Type I IFNs help the immune response by inhibiting viral replication within cells of the body these proteins are mainly metabolized in the liver and kidneys. Since type I IFNs can affect the CYP450 system, a wide variety of interaction studies with proteins of this class have been conducted. The following are some examples of type I IFN's impact on the CYP450 system and on drug interactions.

David Rodrigues and Shekman L Wong

Application of Human Liver Microsomes in Metabolism-Based Drug-Drug Interactions In Vitro-in Vivo Correlations and the Abbott Laboratories Experience can differentially interact with any number of drugs (Burchell et al, 1991 Nelson et al, 1993 Vatsis et al., 1995 Lawton et al., 1994). If multiple drugs interact with the same DME, then the likelihood of a potentially hazardous drug-drug interaction is greatly increased, especially if one of the drugs exhibits a relatively narrow therapeutic index or a steep dose-response profile (Fig. 1). In a safety- and cost-conscious drug development environment, many pharmaceutical companies have seized on this type of information and are now routinely using data from in vitro human metabolism studies as part of their submissions to various regulatory agencies. In turn, these agencies have acknowledged the utility of this information, both in terms of assessing drug safety and approvability (Temple, 1993 Peck et al, 1993).

Clinical pharmacology The interferons

Drug Interactions According to the product label, interactions between Intron A and other drugs have not been fully evaluated. Caution should be exercised when administering Intron A therapy in combination with other potentially myelo-suppressive agents such as zidovudine. Concomitant use of alfa interferon and theophylline decreases theophylline clearance, resulting in a 100 increase in serum theophylline levels.

Pharmacokinetic Interactions

Because the tertiary tricyclics are metabolized by several pathways (CYP1A2, 3A4, 2C19), a selective inhibitor of one pathway would be likely to have less of an effect on these compounds. Drug interactions with the tertiary amines do occur but appear to be less robust. Methylphenidate appears to inhibit demethylation of imipramine to desipramine. At this point, numerous drug interactions have been described, although many are of doubtful clinical significance (for comprehensive reviews, see Nemeroff et al. 1996 Pollock 1997). The other type of pharmacokinetic drug interaction is enzyme induction. The result of this interaction may render the drug acted upon ineffective. Unlike enzyme inhibition, which occurs quickly, enzyme induction requires synthesis of new enzyme. As a result, the full effect of an enzyme inducer may take 2-3 weeks to develop. If the inducer is discontinued, the effect takes 2-3 weeks to dissipate. Barbiturates and carbamazepine are potent inducers of CYP3A4....

A NNRTIs in Current Clinical

This induction also creates the potential for clinically significant drug interactions. Nevirapine decreases the plasma levels of rifampin and rifabutin and certain HIV-1 protease inhibitors including saqinavir and indinavir. Thus, nevirapine+protease inhibitor combination therapy is unlikely to be of use.

FDA Decision Tree Base on In Vitro Studies

Cheng YC, Prusoff WH (1973) Relationship between the inhibition constant (&) and the concentration of inhibitor which causes 50 per cent inhibition (iso) of an enzymatic reaction. Biochem Pharmacol 22 3099-3108 FDA Draft Guidance for Industry on Drug Interaction Studies-Study design, data analysis, and implication for dosing and labeling. September 2006 Kanamitsu SI, Ito K, Sugiyama Y (2000) Quantitive prediction of in vivo drug-drug interactions from in vitro data based on physiological phar-macokinetics use of maximum unbound concentration of inhibitor at the inlet to the liver. Pharm Res 17 336-343 Mayhew BS, Jones DR, Hall SD (2000) An in vitro model for predicting in vivo inhibition of cytochrome P450 metabolic intermediate complex formation. Drug Metab Dispos 28 1031-1037 McGinnity DF, Berry AJ, Kenny JR, Grime K, Riley RJ (2006) Evaluation of time-dependent cytochrome P450 inhibition using cultured human hepa-tocytes. Drug Metab Dispos 34 1291-1300 Obach RS, Walsky RL,...

Methods for studying in vitro metabolism enzyme sources

Variability Potential drug-drug interactions Note For reviews, see articles by Boobis, A. R. , Kremers, P. , Pelkonen, O . , and Pithan, K . , Eds . , EUR 18569 European Symposium on the Prediction of Drug Metabolism in Man Progress and Problems, Luxembourg, Office for Official Publications of the European Communities, 332 pp . , 1999 Boobis, A. R. , Prediction of inhibitory drug-drug interactions by studies in vitro, in Advances in Drug Metabolism in Man, Pacifici, G . M. and Fracchia, G . N . , Eds . , Office for the Official Publications of the European Communities, Luxembourg, 1995, pp. 513-539 and von Moltke, L L et al , In vitro approaches to predicting drug interactions in vivo, Biochem. Pharmacol., 55, 113, 1998. See also Andersson, T. B. et al . , An assessment of human liver-derived in vitro systems to predict the in vivo metabolism and clearance of almokalant, Drug Metab. Dispos., 29, 712, 2001 Pelkonen, O . et al . , Carbamazepine a blind assessment of CYP-associated...

Highthroughput screening in drug metabolism

In general, in vitro-in vivo scaling consists of two approaches prediction of the intrinsic clearance (Clint) of an NCE and prediction of drug-drug interactions . In the literature, methods for both purposes are extensively presented and discussed in the light of actual experimental or clinical studies .41418 It has to be stressed that these extrapolations contain a number of uncertainties, which have to be acknowledged Other pharmacokinetic parameters and characteristics, such as plasma protein binding, the differential binding to various tissues, volume of distribution, and extra-hepatic routes of clearance, should also be considered for the estimation of in vivo kinetics on the basis of in vitro studies . 19 20

Summary and Future Possibilities

Drug targeting preparations are designed to be used in man, however most research with these preparations is carried out in animals. Due to known species differences, the study of these preparations in man in an early stage of development is therefore of paramount importance. In vitro studies exploiting human tissue can be used to ensure that these drug targeting devices reach the desired target cells and once there, are effective. When cells in the liver are the main target, in vitro research should be undertaken using preparations of both healthy and diseased human liver. As was discussed earlier in this chapter, liver slices seem like the ideal in vitro preparation for this purpose. The original architecture of the liver is still intact in the slice, which enables normal intercellular communication and cell-selective distribution of drugs. Slices can also be used to study drug interactions and the mechanisms and

Perspectives And Future Directions

Conducting pharmacokinetic drug-drug interaction studies of therapeutic proteins and peptides are complicated. Because of long half-lives of some of these molecules, such as monoclonal antibodies, conventional crossover studies with adequate washout periods can be difficult to design and conduct. With the advent of therapeutic biological products, the use of these products in clinical conditions such as leukemia, lymphoma, solid tumor cancers, organ transplants, and autoimmune diseases is rapidly growing. The patients with aforementioned disease states may also require concurrent use of other medications. As a result, there is always a potential for drug interactions therefore, a more routine investigation of pharmacokinetic drug-drug interaction studies for new therapeutic biological products is necessary. In a recent paper, Seitz and Zhou (52) have emphasized the importance of drug-drug interaction studies for therapeutic monoclonal antibodies and state the following To successfully...

Pain Assessment in the Elderly

The assessment of pain requires time and patience. Thorough history and physical examination are a crucial part of the assessment. First interview should focus on vital signs, state of hydration, and conversation style of the patient. If these patients are confused or show memory deficit or incoherent speech, then bedside psychological tests should be done to diagnose cognitive deficit. Elderly patients who have difficulty communicating with clinicians are at particular risk of under treatment (Bernabei et al. 1998, Pargeon and Hailey 1999, Fineberg 2006). Detailed chronological history may be collected from the patient, previous medical records or if patient shows memory difficulties or uncooperative behavior, direct interview of family members or caregivers residing with the patient. Systematic physical examination of body should be part of the pain assessment protocol. As most elderly patients suffering from pain are on multiple medications, adverse drug interactions should be kept...

Table 102 Advantages of urine drug testing in clinical pain management practice

Additionally, clinicians will be held accountable for updating such systems and tracking medications prescribed by other treating sources through the data bank. In this way, the clinicians will be expected to review the controlled substances that have already been prescribed, avoid overprescribing, and monitor for potential untoward reactions and drug interactions. Unfortunately, such measures can impose a greater burden on clinicians with regard to tracking patient treatment. Further, there may be greater liability for clinicians for

In Vitro Applications

Another higher throughput in vitro assay is the human cytochrome P450 enzyme inhibition assay. This assay is used to make sure that a compound does not have the potential for producing drug-drug interactions in a clinical setting due to the inhibition of one or more human P450 isozymes 61-66 . Often, these P450 assays are carried out in a higher throughput manner using 96-well plates

Current Clinical Treatments of AIDS

The treatment of HIV infection has always posed a unique challenge. The number of medications, their various formulations and combinations, their potential toxicities, and drug-drug interactions make HIV one of the most difficult diseases to manage. In the past 11 years, however, there have been dramatic improvements in HIV therapy. Patients with access to newer medications have drastically reduced rates of HIV-related morbidity and mortality. These patients, largely in the United States and other developed countries, have found their quality of life improved with simpler regimens of less toxic medications. This chapter, in the first section, will focus on each Food and Drug

Pain Management Considerations

The frequent comorbidities seen in the elderly often results in polypharmacy. The effect of drug interactions and the altered handling of drugs in the elderly increases the risk of complications. Caution has to be exercised in developing a management plan with appropriate consideration to side effects and potential interactions.56 Other chapters detail the management of specific conditions and discuss the pharmacology of individual drug groups. In a general sense, the World Health Organization (WHO) analgesic ladder can guide initial pain management. There is a principle in prescribing, particularly in the elderly, to start with a low dose and slowly titrate to benefit or side effects. The aim of pain management is to improve pain and optimize function, particularly with regard to daily activities. The eradication of pain is usually unrealistic and the lowest drug dose will often not provide optimal analgesia. Optimal treatment typically combines pharmacological and nonpharmacological...

Pharmacological Effects

Ephedra has been closely linked to methamphetamine production. There are movements in many localities to outlaw the herb. There are many drug interactions with ma huang. S-Blockers may enhance the sympathetic effect and cause hypertension. MAOIs may interact with ephedra to cause hypertensive crisis. Phenothiazines might block the a-effects of ephedra, causing hypotension and tachycardia. Simultaneous use of theophylline may cause GI and CNS effects. In pregnancy, ephedra is absolutely contraindicated (uterine stimulation). Persons with heart disease, hypertension, and diabetes should not take ephedra.

Synthesis Of Zolantidine

Synthesis Zolantidine

Sir James Black and colleagues synthesized and characterized the first H2 receptor antagonists, unequivocally demonstrating the existence of more than one type of HA receptor (Black et al. 1972). The work showed clearly a physiological role for gastric HA and revolutionized the treatment of peptic ulcer disease. Presently, there are four H2 antagonists in wide clinical use cimetidine, ranitidine, famotidine, and nizatidine. Surprisingly, cimetidine's Kd on the H2 receptor is only 0.8 M (Hill et al. 1997), yet the drug has been used successfully by millions of patients with only a few side effects. Cimetidine is known to inhibit some forms of cytochrome P450, which can lead to clinically significant drug-drug interactions (Furuta et al. 2001). Many other non-H2 actions of cimetidine have been found at higher drug concentrations (see table 3 in Hough et al. 1997). Because of its low potency and non-H2 actions, cimetidine is not a good experimental agent to study H2 receptor actions....

PGlycoprotein Pgp ABCB1

While the observed absorption of numerous drugs may be affected by P-gp affinity, there are certain drugs that can also be used to inhibit P-gp activity (Krishna and Mayer, 2000). The P-gp inhibitors include several calcium channel blockers, immunosuppressive agents, and other well-characterized compounds such as SDZ, PSC 833, LY335979, and GF120918 (Table 7.2) (Hyafil et al., 1993 Schinkel and Jonker, 2003). Drug-drug interactions resulting from concomitant administration of P-gp substrates and or inhibitors may result in an increase in the absorption of one or more of these agents, potentially leading to toxic side effects by virtue of increased plasma levels that rise above the minimum toxic concentration. There are numerous clinical examples of these effects being observed and reported in the literature. For example, a significant therapeutic increase in the plasma levels of digoxin was observed upon coadministration with valspo-dar (PSC833) in healthy patients. The increase in...

O Newer Agents For The Treatment Of Hiv Infection

Ritonavir (Norvir),98 amprenavir (Agenerase),99 and nelfinavir (Viracept)100 have similar properties and cautionary statements. All cause dyslipidemia, and they have a host of drug interactions, mainly because they inhibit CYP3A4. These agents must always be used with at least two other antiretroviral agents. Used properly, the PIs are an important part of HIV therapy.

Discovery and Preclinical Development Candidate Selection

In vitro ex vivo techniques to assess ADME properties include in vitro CYP screens to assess potential for metabolic liabilities and drug interactions, transporter screens against known targets and efflux pumps, in vitro metabolism in the presence of isolated hepatocytes or microsomes (various species to assess inter-species differences), and transport across cell culture model systems as surrogates for passive membrane transport. These screens are used to eliminate candidates with a high potential for ADME liabilities that could negatively impact utility in a clinical setting. Preclinical ADME studies in vivo using various animal models are also necessary to assess blood concentration-time profiles, AUC, BA, Cmax, tmax, dose proportionality, accumulation upon multiple dosing or enzyme induction. Intravenous delivery is necessary for determining absolute BA, clearance, and volume of distribution. Specialized studies can be designed to better understand the fundamental mechanisms of...

Clinical Consequences of the Effects of Interferons on the CYP450 System

The aforementioned studies provide some evidence that type I IFNs may inhibit or induce hepatic drug metabolism in humans and there may be some potential of toxic drug-drug interactions. However, the studies also indicate that inhibition or induction may not be of any clinical significance mainly because of the high variability and bidirectionality (inhibition in some subjects and induction in some). Because of limited number of interaction studies and since these studies were only short-term studies, it is very difficult to make an outright conclusion about the clinical consequences of these studies.

PH Bile Salts and Proteins for Biorelevance pH Adjustment

Yamashita and coworkers studied the effect of medium pH on the transport rate of several passively and actively transported drugs in Caco-2 cells (including antipyrine, theophylline, hydrochlorothiazide, atenolol, terbutaline, nadolol, salicylic acid, furosemide and cephalexin). Transport was studied in the absence (apical and basolateral medium buffered at pH 7.4) or presence (apical medium buffered at pH 6.0, basolateral medium buffered at pH 7.4) of a pH-gradient. The observed differences in apparent permeability were attributed to both difference in drug partitioning and modification of carrier-mediated transport (Yamashita et al., 1997). A similar study was run in the PAMPA model (Sugano et al., 2001). The permeation of 30 model compounds, expected to be passively tran-scellularly transported, was assessed as a function of pH. For both models, it was concluded that a better prediction of the fraction absorbed in humans would be obtained under pH-gradient conditions. Although...

Pharmacological Models for Antitubercular Drugs

Finally, the use of therapeutic drug monitoring (TDM) has been a useful tool for assessing drug levels during treatment in the clinical setting 71 . The use of TDM in tuberculosis treatment can allow physicians the ability to adjust dosing to provide an efficacious therapeutic concentration throughout the extensive duration of treatment 71 . Patients who most benefit are those with complications which may alter drug exposure, such as those on co-therapy for HIV for which there are known drug-drug interactions, those with diabetes mellitus with typical delayed absorption or malabsorption concerns, those with renal failure undergoing dialysis, and those experiencing hepatic dysfunction (see Sect. 1.4) 69 . TDM in combination with bacteriological and clinical data can be a useful tool to assess treatment and ensure as successful outcome 71 .